Project Summary: Precision approaches for inhibiting, preventing recurrence, or treating cancers remains a top priority in the US. While different inhibitors have made significant improvements for these purposes (e.g. immune checkpoint inhibitors, growth factor receptor inhibitors, etc.), it is clear that additional molecular targets are needed to combine with these existing therapies due to the heterogeneity of cancers and the fact that many cancers are resistant to different inhibitors. Thus, delineating new molecular mechanisms for combinatorial approaches for more precision inhibition and therapy of cancer is of high significance. The peroxisome proliferator-activated receptor-?/? (PPAR?/?) has great potential as a molecular target for preventing and/or treating colorectal cancer (CRC). Typical ligands for PPAR?/? increase and decrease target gene expression. However, more selective, repressive PPAR?/? ligands have recently been developed that only repress gene expression rather than increase target genes. These selective repressive PPAR?/? ligands can markedly inhibit cellular events associated with cancer inhibition, progression and metastasis. There is no dispute that selective, repressive PPAR?/? ligands are effective anti-cancer molecules. These facts and preliminary data provide strong support and rigor of the central hypothesis of this proposal that repressing PPAR?/? target genes by a selective, repressive ligand can modulate CRC and may be targeted for precision approaches to inhibit/treat CRC. This hypothesis will be examined by 3 Aims. Aim 1 will include PK analysis of the selective, repressive PPAR?/? ligand DG172 of tissue concentrations over time, and phase I and phase II metabolism of the selective, repressive PPAR?/? ligand in tissues, biofluids and tumors. Aim 2 will determine the efficacy of the selective, repressive PPAR?/? ligand DG172 to inhibit tumorigenesis and stemness in novel orthotopic tumors models that utilize unique, genotypically variant human cancer cell lines with genotypes that exhibit resistance to standard inhibitors used to treat CRC, and gain- and loss-of-function models for PPAR?/?. The mechanisms by which PPAR?/? regulates stemness will also be determined. For Aim 3, we will integrate genomic and metabolomic bioinformatic analyses to elucidate how specific metabolic and tumor-promoting pathways that can be targeted by selective repressive PPAR?/? ligands to inhibit CRC progression and treat CRC. Data from Aim 3 will be made available to scientists by developing a web-based platform to allow for systems analyses of PPAR?/?-specific pathways that inhibit CRC. Results from these studies will have a sustained impact as they will provide new PPAR?/?-dependent targets that might be combined with other inhibitors to develop more effective therapies, and prevent recurrence, for CRC.